1. Field of the Invention
The invention relates to a synthetic peptide which mimics the biological properties of nerve growth factor (NGF) and is useful for treating neurological disorders.
2. Background of the Invention
Nerve growth factor (NGF) was discovered more than forty years ago by Levi-Montalcini et al. in malignant tissues. Subsequently Cohen isolated NGF from snake venom and then from sub maxillary gland of mouse, a homolog to the snake venom gland. Since the discovery it was contemplated that NGF will be clinically useful to treat neurological disorders, like Alzheimer's (AD), Parkinson's (PD) and other neurological diseases. Over the years, several neurotrophic factors such as NT-3, bFGF, platelet derived growth factor, etc. were discovered. These factors regulate nerve cell growth and survival.
Research in animals has demonstrated that neurotrophic factors delivered to central nervous system can prevent or reverse neurodegeneration. Generally, neurotrophic factors cannot cross the blood-brain barrier due to their size and therefore, will not reach the brain when administered either orally or through injection. As a result, researchers have administered these proteins directly into the brain to determine their effectiveness in combating neurodegenerative diseases. In animals, various neurotrophic factors administered through a hole drilled into the scull have been successful in restoring memory and stimulating nerve regeneration. In humans, nerve growth factor administered in similar way has improved memory in Alzheimer's disease patients.
A more convenient delivery system is required, to produce the beneficial effects that have been established for neurotrophic factors. The selective breakdown of the blood-brain barrier has not proven to be effective as yet. The most practical approach is to mimic the effects of neurotrophic factors by administration of an orally active compound that passes the blood-brain barrier and produces the effects of neurotrophic factors in the brain or turns on the genes to produce neurotrophic factors at the site where they are needed in the brain.
AIT-082 is the first compound that has entered human clinical trials, which has been demonstrated to activate multiple genes in animals to produce three different neurotrophic factors (NGF, NT-3 and bFGF) in the specific areas of the brain associated with memory loss. In addition, AIT-082 has the advantage of being rapidly absorbed and active after oral administration. However, its efficacy remains to be determined.
Appel proposed that selective neuronal degeneration may be caused by failure of target tissues to supply the necessary neurotrophic factor. A specific link between NGF and AD was first suggested by Hefti. It has been reported that NGF level rises in pathological situation such as hypoxic injury in adult rats. Data are already emerging to suggest an age-related reduction in both NGF and its receptor in rat brain.
Naturally occurring bioactive peptides have been proposed for neurological disorders. Appel and Tomozawa 1991 isolated, extracted and purified three different neurotrophic factors from caudate putmen tissue of normal mammal, to treat amyotrophic lateral sclerosis (ALS), PD and AD. Heinrich produced recombinant human (h-NGF) made in Chinese hamster ovary cells. (CHO). Lewis et al. 1992 proposed the use of insulin like growth factor for treating disorders enhancing the survival of non-mitotic cells.
Despite the previous failures to obtain NGF in animal sera, at Ophidia Products we have successfully isolated NGF from human and other animal sera, showing neurotrophic activity when tested on PC12 cells. In addition, we have isolated NGF from human saliva and urine. Furthermore, we have isolated NGF from the established cultures of eukaryotic cells; Chang cells (human liver), Vero (monkey kidney), pheochromocytoma PC12 (rat adrenal gland), neuroblastoma (human brain) and mouse myeloma (SP/2) cells.
According to Wells, 1996 the commonly held view that small synthetic peptides cannot mimic effects of large polypeptide ligands is by now considerably out of date. Several investigators have made synthetic NGF peptide derivatives which prevent neuronal death and show neurite outgrowth, the characteristic of the neurotrophic factor on PC12 cells. Longo et al. (1997) made cyclized peptides corresponding to beta loop region of NGF and found the highest activity corresponding a loop region 29-35 which is capable to interact with p75 receptor. According to them, to this date, no small molecule NGF agonist or partial agonists agents known to promote neurotrophic effects by acting via NGF receptors have been described.
A small molecule which behaves like NGF would be very desirable for treating neurological disorders, since it would overcome the blood-brain barrier. It would be capable of reaching the brain by most any route, for example, intramuscular, intravenous, buccal cavity or nasal insufflation could be used. It may avoid triggering antibody production.
A small molecule which behaves like NGF and can be synthetically produced would be even more desirable, since its production would be straightforward and inexpensive.